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Synthesis of indolines by a Zn-mediated Mannich reaction / Pd-catalyzed amination sequence Marc Presset, Antoine Pignon, Jérôme Paul, Erwan Le Gall, Eric Leonel, and Thierry Martens J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00013 • Publication Date (Web): 24 Feb 2017 Downloaded from http://pubs.acs.org on February 24, 2017

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The Journal of Organic Chemistry

Synthesis of indolines by a Zn-mediated Mannich reaction / Pd-catalyzed amination sequence

Marc Presset, Antoine Pignon, Jérôme Paul, Erwan Le Gall,* Eric Léonel, Thierry Martens

Électrochimie et Synthèse Organique, Université Paris Est, ICMPE (UMR 7182), CNRS, UPEC, 2-8 rue Henri Dunant, F-94320 Thiais, France

[email protected]

Abstract 1,2-Disubstituted indolines have been prepared in fair to good yields by a Zn-mediated organometallic Mannich reaction followed by an intramolecular Pd-catalyzed aromatic amination. The reactions are easy to set up and compatible with a large variety of simple or commerciallyavailable reagents. The method was further extended to the preparation of a 1,2,3-trisubstituted indoline.

The indoline scaffold is an important structural motif for medicinal chemists as it can be found in numerous naturally occurring alkaloids such as strychnine or oleracein A–D and in other bioactive compounds such as pentopril (Figure 1).1,2,3 These attractive properties have made indolines relevant targets for the organic chemists' community.4 Apart from the hydrogenation of indoles, main synthetic strategies towards indolines are based on the construction of the pyrrolidine ring system. For instance, the Pd-catalyzed heteroannulation of dienes with o-iodoanilines has been introduced by Larock in 1990.5 This method has been recently improved by Jamison through extension to terminal alkenes using dual Ni/photoredox catalysis,6 while Glorius developed the use ACS Paragon Plus Environment


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of alkenes in Rh(III)-catalyzed C–H activation/alkene insertion reactions.7 A more general route has been pioneered by Buchwald, using a Pd-catalyzed intramolecular amination reaction between an aryl halide and an amine.8,9,10 The main advantages of this strategy are the use of mild reaction conditions and a great functional group tolerance. However, it requires the preparation of orthohalogenated β-arylethylamines bearing both reactive sites, usually by means of a multiple-step linear synthesis. Although few of the usual synthetic methods could approach the high degree of modularity reached by multicomponent reactions (MCRs),11 exploitation of this class of reactions for the preparation of indolines precursors has not been exploited so far. Based on our experience in MCRs involving organometallic species,12,13 we anticipated that ortho-halogenated β-arylethylamines required for the preparation of indolines could be prepared by an organometallic Mannich reaction involving an ortho-brominated benzyl bromide.14,15,16 Therefore, we describe herein a general two-step sequence involving a Zn-mediated Mannich reaction and a Pd-catalyzed intramolecular amination for the synthesis of 1,2-di- and even 1,2,3-trisubstituted indolines.

Figure 1. Selected bioactive indolines

We began our study with the optimization of the organometallic Mannich reaction between commercial or easily accessible ortho-brominated benzyl bromides 1, primary amines 2 and aldehydes 3. Based on previous studies,17,18,19 we turned our attention to Zn-mediated transformations as this metal proved efficient for the metalation of benzylic carbon-halogen bonds. A preliminary experiment using 2-bromobenzyl bromide 1a (2.0 equiv), aniline 2a (1.0 mmol) and 4-tolualdehyde 3a (1.0 equiv) in the presence of zinc dust (2.0 equiv) in acetonitrile at ambient ACS Paragon Plus Environment

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temperature afforded the expected compound 4a in 68%. This result revealed that 1a was chemoselectively activated at the benzylic position without alteration of the aromatic C–Br bond. This information was consistent with previous reports by Gosmini indicating that zincation of aromatic carbon-halogen bonds requires the use of an additional cobalt catalyst.20 We next found the addition of TFA to activate Zn was beneficial for the reaction with an increased yield of 90% whereas the use of THF as the solvent or Mn as the reductant were deleterious (59% yield and no reaction, respectively). The requirement of an excess (> 2.0 equiv) of the organozinc reagent to obtain the desired ortho-halogenated β-arylethylamine 4 in useful yields was confirmed by the decreased yield (58%) observed when the reaction was performed with only 1.5 equiv of 1a.21 We then turned our attention to the scope of the reaction and the results are reported in Table 1.

The Zn-mediated organometallic Mannich reaction proved general for the preparation of orthobrominated β-arylamines 4.22 Using commercially available 2-bromobenzyl bromide (1a) as a starting material, a large variety of primary amines underwent the reaction even if small amines such as allylamine and n-propylamine afforded lower yields of coupling products (4c and 4d), presumably due to their volatility under such exothermic conditions. The reaction also tolerated various aldehydes including aromatic (products 4a-f, 4i and 4o-p), heteroaromatic (product 4g) or aliphatic aldehydes (product 4h) in moderate to decent yields. However, the expected reaction was not observed with primary amides, ketones, pivaldehyde or methyl pyruvate. Substitution at the aromatic ring of the dibromide 1 with electron-neutral or electron-withdrawing groups was also possible (products 4i and 4j), but the introduction of an electron-donating group led only to traces of the desired product. Importantly, the present protocol was also compatible with the use of ethyl glyoxylate (3f) as the aldehyde partner, affording the corresponding α-aminoester derivatives in useful yields (products 4j-m). The diastereoselectivity of the multicomponent reaction was also evaluated using commercial chiral substrates. Therefore, when (–)-menthyl glyoxylate (3g) was used, the expected product 4n was obtained but only with moderate stereoinduction (dr=1.7:1). On

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the other hand, when (R)-α-methylbenzylamine (2f) was used, the secondary β-arylethylamine 4o was obtained in 65% yield with a fair diastereoselectivity (dr=3.8:1). The importance of the chiral group linked to the amine function was confirmed by the reaction performed with (S)-1-(1naphthyl)ethylamine (2g) which displayed a slightly higher diastereoselectivity (dr=4.3:1).

Table 1. Multicomponent synthesis of ortho-brominated β-arylethylaminea

a

Yields of isolated products. Reaction conditions: 1 (2.5 equiv), 2 (2.5 mmol), 3 (1.1 equiv), Zn

(3.75 equiv), TFA (25 mol%), CH3CN (C=0.5 M), 1 h;

b

Reaction conditions: 1 (2.0 equiv), 2

(1.0 mmol), 3 (1.0 equiv), Zn (2.0 equiv), TFA (10 mol%), CH3CN (C=0.5 M), 16 h; c Reaction


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performed under conditions b with 3a (3.0 equiv) and Zn (3.0 equiv);

d

Diastereoisomeric ratio,

determined by 1H NMR analysis.

The cyclization of these β-arylethylamines 4 was undertaken by intramolecular aromatic amination. After a screening of diverse catalysts under varied conditions, the use of 5 mol% of PdCl2(PPh3)2 with 2.0 equiv of potassium tert-butylate in refluxing toluene was identified as a very efficient catalytic system. The conversion of precursors 4 into the corresponding indolines was thus performed under such conditions and the results are reported in Table 2. These conditions proved to be general and afforded the desired indolines 5 in fair to good yields (products 5a-i), regardless of the nature of the substituent of the pyrrolidine ring. However, although this set of conditions proved to efficiently deliver most of the target indolines, phenylalanine derivatives 4j-n showed no conversion under standard conditions. Considering the presence of an enolizable ester group on the starting substrate, the base was thus changed to the less alkaline cesium carbonate and the solvent was switched from toluene to tetrahydrofuran. These modifications proved relevant, as the corresponding cyclization products 5j-n were thus obtained in decent to good yields. Importantly, none of these conditions provoked either aromatization or erosion of diastereoisomeric ratios observed during the Mannich step (products 5n-p).

Table 2. Pd-catalyzed cyclization of β-arylethylaminesa



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a

Yields of isolated products. Reaction conditions: 4 (0.5 mmol), PdCl2(PPh3)2 (5 mol%), t-BuOK

(2.0 equiv), toluene (C=0.2 M), 110 °C, 14 h; b The free indoline resulting from hydrodeallylation is concomitantly obtained in 19% yield; c Reactions performed using Cs2CO3 in THF at 80 °C for 24 h; d Diastereoisomeric ratio determined by 1H NMR analysis.

Extension of this two-step strategy to the preparation of a 1,2,3-trisubstituted indoline required additional investigations. Indeed, the use of the above-mentioned conditions for the preparation of indolines precursors starting from secondary benzyl bromide 1d only led to traces of the desired product together with major amounts of dimeric side-products. It was noticed that a decrease of the


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reaction temperature to 0 °C and dropwise addition of the dihalogenated starting material favors the desired multicomponent coupling. Under such conditions, the reaction between substrate 1d, benzylamine (2b) and 4-tolualdehyde (3a) afforded a correct 50% isolated yield of 4q with a moderate diastereoselectivity (Scheme 1).23 The following intramolecular amination step, which was realized under the same above-mentioned conditions, led to the corresponding 1,2,3trisubstituted indoline 5q in very good yield (86%), without modification of the diastereoisomeric ratio.

Scheme 1. Synthesis of a 1,2,3-trisubstituted indoline

To ascertain that this method can represent a reliable route to substituted indoles, a tentative oxidation of indolinic α-amino ester 5k to the corresponding indole 6 was undertaken using manganese oxide. The oxidized compound was obtained in an excellent 90% yield after 4 days in refluxing toluene (Scheme 2).

Scheme 2. Oxidation of indoline 5k to indole 6 CO2Et N Ph 5k

MnO2 (4.0 equiv) toluene, 110 °C, 96 h

CO2Et N Ph 6, 90%

In conclusion, we present herein a straightforward two-step procedure for the generation of diversely substituted indolines starting from commercial or easily accessible substrates. The tolerant and modular character of the method is ensured by an organometallic Mannich reaction followed by an intramolecular amination that allows the facile synthesis of 1,2-disubstituted indolines. The ACS Paragon Plus Environment


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present methodology was also demonstrated efficient for the preparation of indolinic α-amino esters and of a 1,2,3-trisubstituted indoline.

Experimental Section General considerations: All commercially available reagents were used as received. In particular, zinc dust (

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